BACKGROUND: Dapagliflozin is a selective sodium-glucose co-transporter-2 inhibitor (SGLT-2i) that reduces blood glucose, weight and blood pressure by promoting glycosuria via inhibiting urinary glucose reabsorption. Previous SGLT-2i trials have demonstrated statistically significant reductions in the combined primary outcome of CV death, MI and stroke (MACE), primarily in patients with known atherosclerotic CVD, and have demonstrated reductions in hospitalization for heart failure (HHF).
METHODS: DECLARE - TIMI 58 [NCT01730534] is a phase 3b randomized, double-blind, placebo-controlled trial to evaluate the CV safety and efficacy of dapagliflozin in patients with type 2 diabetes mellitus (T2DM) and either CVD or multiple risk factors (MRF) for CVD. Patients were randomized 1:1 to dapagliflozin 10 mg or matching placebo. The primary safety outcome is MACE. The dual primary efficacy outcomes are MACE and the composite of HHF or CV death. This event-driven trial was planned to randomize approximately 17,000 subjects and continue until at least 1390 adjudicated MACE events occurred. This event number provides >99% power for the safety outcome to reject the hypothesis that the upper bound of the confidence interval is >=1.3. There will also be approximately 80% power to detect a 15% relative risk reduction in MACE and 80% power for a 20% reduction in the composite of HHF or CV death, each at two-sided alpha levels of 0.0231. If one of the efficacy endpoints is significant, the alpha will be recycled, allowing testing of the other endpoint at a two-sided alpha of 0.0462, providing at least 85% and 87% power, respectively.
RESULTS: DECLARE - TIMI 58 randomized 17,160 patients (6974 w/ CVD and 10,186 w/ MRF). The trial has met its planned number of endpoints and database lock is anticipated in September, 2018. At the AHA we plan to present the primary efficacy and safety results.
CONCLUSIONS: DECLARE - TIMI 58 is testing the hypotheses that dapagliflozin is safe and will reduce the occurrence of important CV events. DECLARE - TIMI 58 is the largest trial with an SGLT-2i to address these questions in a broad population of patients with T2DM and includes participants both with established CVD and those without CVD, but with multiple CV risk factors.